Throughout the application, various publications are referenced in parentheses. The disclosures of these publications in their entireties are hereby incorporated by reference in the application in order to more fully describe the state of the art to which this invention pertains.
1. Field of the Invention
The present invention is related to the medical arts, in particular to the treatment of pituitary tumors.
2. Discussion of the Related Art
The pituitary gland is divided into two primary regions, a larger anterior region (adenohypophysis), which constitutes 80 percent of the pituitary by weight, and a smaller posterior region (neurohypophysis). This gland connects to a region of the brain called the hypothalamus near the pituitary stalk. Because of its close proximity to major intracranial nerves and blood vessels, as well as the vital hormonal control the pituitary gland provides, disorders of the pituitary can cause a wide spectrum of symptoms, both hormonal and neurological. In most instances, pituitary disorders result in the secretion of either too much or too little of one or more hormones typically secreted by the pituitary gland.
The importance of the pituitary gland is amply illustrated by the numerous hormones it produces, i.e., hormones such as Thyroid Stimulating Hormone (TSH), Growth Hormone (GH), Adrenocorticotrophic Hormone (ACTH), Antidiuretic Hormone (ADH), Luteinizing Hormone (LH), Prolactin (PRL), Follicle Stimulating Hormone (FSH), Melanocyte-Stimulating Hormone (MSH), and Oxytocin.
The cells of the anterior lobe synthesize and release several protein hormones necessary for normal growth and development and also stimulate the activity of several target glands. Deviations above or below normal hormone levels of the hormones produced by the anterior lobe can result in any one of a number of disease conditions. For example, excess amounts of the hormone ACTH can result in Cushing""s syndrome; an excess production of TSH causes hyperthyroidism; and hypersecretion of GH can result in either acromegaly or gigantism. Conversely, reduced amounts of GH can cause growth hormone deficiency syndrome in adults and children, (characterized by short stature in children). Other hormones controlled by the anterior lobe include LH and FSH, which when affected by a tumor can give rise to sexual symptoms in men and women. Increased production of prolactin can cause abnormal milk production, irregular menses and infertility in women; for men, increased prolactin levels can cause impotence, infertility, feminization and lactation. Tumors affecting the posterior lobe disrupt production of ADH, which may lead to diabetes insipidus; the hormone oxytocin is also secreted from the posterior lobe.
Some pituitary disorders have exhibited a familial predisposition, including, e.g., multiple endocrine neoplasia, Carney complex, and McCune Albright syndrome. (See Larsson, C., et al., M. Multiple endocrine neoplasia type 1 gene maps to chromosome 11 and is lost in insulinoma, Nature 322:85-87 [1988]; Chandrasekharappak, S. C., et al., Positional cloning of the gene for multiple endocrine neoplasia- type 1, Science 276:404-406 [1997]; Stratakis, C. A., et al., Carney complex, familial multiple neoplasia and lentiginosis syndrome. Analysis of kindreds and linkage to the short arm of chromosome 2, J. of Clin. Invest. 97:699-705 [1996]; Lyons J., et al., Two G protein oncogenes in human endocrine tumors, Science 249:655-659 [1990]).
One genre of pituitary disorders is pituitary tumors. A pituitary tumor (adenoma) is a non-cancerous growth that typically affects different hormone-producing regions, depending on its specific location. Pituitary tumors account for about 15% of intracranial tumors, and are associated with significant morbibity due to local compressive effects, hormonal hypersecretion, or treatment-associated endocrine deficiency (Heaney A. P., et al.: Molecular Pathogenesis of Pituitary Tumors. In: Oxford Textbook of Endocrinology, Wass J. A. H. and Shalet S. M., (Eds.), Oxford University Press, Oxford, 2002 (in press)). The great majority of pituitary adenomas are benign, not malignant, and are relatively slow growing. (See UCLA Neurosurgery web site at  less than www.neurosun.medsch.ucla.edu greater than ). Pituitary tumors may lead to overproduction of one or more of the pituitary hormones. In other instances, pituitary tumors are non-functioning or xe2x80x9cendocrine-inactive,xe2x80x9d meaning that they do not produce excessive hormones.
Non-functioning adenomas are the most commonly encountered pituitary tumors. These tumors fail to secrete hormones, are generally macroadenomas (xe2x89xa71 centimeter), and cause high morbidity and ultimately mortality due to visual field loss, headache, and pituitary dysfunction (Shimon, I., et al., Management of Pituitary Tumors, Ann. Intern. Med. 129:472-483 [1998]). Some non-functioning pituitary tumors express dopamine and/ or somatostatin receptors, but response to treatment with dopamine agonists and/ or somatostatin is poor, and their use has largely been discontinued (Nobels, F. R., et al., Long-term treatment with the dopamine agonist quinagolide of patients with clinically non-functioning pituitary adenoma. Eur. J. Endocrinol. 143:615-21 [2000]) and effective drug therapies for non-functioning pituitary tumors do not currently exist. As pituitary tumors enlarge, compression of normal pituitary tissue can occur, resulting in decreased or absent hormone production. This condition is called hypopituitarism and may also result from brain trauma, surgery, bleeding into the pituitary or from radiation therapy to the pituitary.
Examples of pituitary tumors that lead to pituitary hormone hypersecretion are PRL- and GH-secreting pituitary tumors. Dopamine agonists and somatostatin analogs effectively suppress PRL and GH hypersecretion, respectively, and control tumor growth or induce tumor shrinkage in most, but not all, PRL-and GH-secreting pituitary tumors (Shimon, I., et al., Management of Pituitary Tumors, Ann. Intern. Med. 129:472-83 [1998]; Giustina, A., et al., Criteria for cure of acromegaly: a consensus statement, J. Clin. Endocrinol. Metab. 85:526-9 [2000]). A subset of patients with PRL- and GH-secreting pituitary tumors do not respond to such drug treatments or are intolerant of side-effects from these drugs. For unresponsive GH- and PRL-secreting, and non-functioning pituitary tumors, surgery with or without adjuvant radiation is the treatment mainstay, and portends a 50-60% overall control rate in specialized centers (Bevan, J. S., et al., Non-functioning pituitary adenomas do not regress during bromocriptine therapy but possess membrane-bound dopamine receptors which bind bromocriptine, Clin. Endocrinol. 25:561-72 [1986]; Colao, A., et al., New medical approaches in pituitary adenomas, Horm. Res. 53:76-87 [2001]). Although 70% of pituitary microadenomas are successfully resected by transsphenoidal approaches, 25% of PRL-secreting, and 90% of GH-secreting and non-functioning tumors are  greater than 1 cm in diameter, and surgical xe2x80x9ccurexe2x80x9d rates for these macroadenomas are achieved in about a third of patients in specialized centers (Colao, A., et al., New medical approaches in pituitary adenomas, Horm. Res. 53:76-87 [2001]). Tumor recurrence requires pituitary-directed radiation to suppress tumor growth and hormonal levels, but radiation effects may not be manifest for several years, and are ultimately associated with pituitary damage and dysfunction in most patients (Kreutzer J., et al., Surgical management of GH-secreting pituitary adenomas: an outcome study using modern remission criteria, J. Clin. Endocrinol. Metab. 86:4072-7 [2001]).
Another such pituitary tumor that leads to pituitary hormone hypersecretion is an ACTH-secreting pituitary tumor. About 90% of ACTH-secreting pituitary tumors are microadenomas ( less than 1 cm diameter), and cavernous sinus invasion or optic chiasm compression are uncommonly encountered (Ross, E. J., et al., Cushing""s syndrome-killing disease: Discrimatory value of signs and symptoms aiding early diagnosis, Lancet 2:646-9 [1982]; Oldfield, E. W., et al., Petrosal sinus sampling with and without corticotrophin-releasing hormone for the differential-diagnosis of Cushing""s syndrome, N. Engl. J. Med. 325:897-905 [1991]). Although ACTH-secreting pituitary tumors are rarely invasive, they cause considerable morbibity due to excess glucocorticoid production. ACTH-secreting lesions cause elevated, non-suppressible, ACTH levels, hypercortisolemia, Cushing""s syndrome, and varied clinical manifestations, including diabetes, hypertension, muscle weakness, and osteoporosis (Ross . E. J., et al., Cushing""s syndrome-killing disease: Discrimatory value of signs and symptoms aiding early diagnosis. Lancet; 2: 646-9 [1982]). Unless treated, the ACTH-secreting pituitary tumors are associated with high morbidity and ultimately mortality (Oldfield E. W., et al., Petrosal sinus sampling with and without corticotrophin-releasing hormone for the differential diagnosis of Cushing""s syndrome. N. Engl. J. Med., 1991; 325: 897-905).
Effective drug therapies for ACTH-secreting pituitary tumors do not currently exist. Surgery with or without adjuvant radiation is the treatment mainstay, and portend a 50-60% overall control rate in specialized centers (Simmons, N. E., et al., Serum cortisol response to transphenoidal surgery for Cushing disease, J. Neurosurg. 95:1-8 [2001]; Mampalam, T. J., et al., Transsphenoidal microsurgery for Cushing""s disease: A report of 216 cases, Ann. Intern. Med. 109:487-93 [1988]; Hoybye, C., et al., Adrenocorticotrophic hormone-producing pituitary tumors: 12 to 22-year follow-up after treatment with sterotactic radiosurgery, Neurosurgery 49:284-91 [2001]).
Cushing""s syndrome is a disease condition in mammals, wherein an increased blood concentration of cortisol (hypercortisolism) or glucocorticoid hormone is present over a long period of time. The most common cause of Cushing""s syndrome is excessive production of ACTH by the pituitary gland. ACTH stimulates the growth of the adrenal glands and the secretion of other corticosteroids. This elevated level of ACTH in the bloodstream typically is produced by a pituitary adenoma (Cushing""s disease), but in rare instances has a different etiology. Cushing""s syndrome resulting from the production of ACTH in a location other than the pituitary gland is known as ectopic Cushing""s syndrome. Examples of ectopic sites include thymoma, medullary carcinoma of the thyroid, pheochromocytoma, islet cell tumors of the pancreas and oat cell carcinoma of the lung. The overwhelming majority of Cushing""s syndrome cases in humans, however, trace their etiology to a pituitary adenoma. Symptoms of Cushing""s syndrome include weight gain, central obesity, steroid hypersecretion, elevated urinary cortisol excretion, moon face, weakness, fatigue, backache, headache, impotence, mental status changes, muscle atrophy, and increased thirst and urination compared to mammals not suffering from this disease.
No medical therapies are currently available for Cushing""s syndrome. In experienced specialized centers, surgical resection of ACTH-secreting pituitary microadenomas offers an overall cure rate of about 70-80%, but for macroadenomas control rates only approximate 30%, and the extensive surgical resection required portends significant risk to surrounding normal pituitary tissue, leading to partial or total hypopituitarism in about 80% of cases (Simmons, N. E., et al., Serum cortisol response to transphenoidal surgery for Cushing disease, J. Neurosurg. 95:1-8 [2001]; Mampalam, T. J., et al., Transsphenoidal microsurgery for Cushing""s disease: A report of 216 cases, Ann. Intern. Med. 109:487-93 [1988]; Trainer, P. J., et al., Transsphenoidal resection in Cushing""s disease: undetectable serum cortisol as the definition of successful treatment, Clin. Endocrinol. 38:73-8 [1993]).
Diagnosis and treatment of Cushing""s syndrome remains a challenge (Oldfield, E. W., et al., Petrosal sinus sampling with and without corticotrophin-releasing hormone for the differential diagnosis of Cushing""s syndrome, N. Engl. J. Med. 325:897-905 [1991]; Findling, J. W., et al., Diagnosis and differential diagnosis of Cushing""s syndrome, Endocrinol. Metab. Clin. North Am., 30:729-47 [2001]; Orth, D. N., Cushing""s syndrome, N. Engl. J. Med. 332:791-803 [1995). Therapy for patients harboring ACTH-secreting adenomas can be directed towards the hypothalamus, pituitary, or adrenal gland. Despite high resolution MR pituitary imaging, and petrosal sinus sampling to establish pituitary-derived ACTH hyper-secretion, pre-operative pituitary tumor localization and lateralization may be difficult (Oldfield, E. W., et al., Petrosal sinus sampling with and without corticotrophin-releasing hormone for the differential diagnosis of Cushing""s syndrome, N. Engl. J. Med. 325:897-905 [1991]; Findling, J. W., et al., Diagnosis and differential diagnosis of Cushing""s syndrome, Endocrinol. Metab. Clin. North Am., 30:729-47 [2001]). Although 70% of pituitary microaderiomas are successfully resected by transsphenoidal approaches, surgical xe2x80x9ccurexe2x80x9d rates for macroadenomas are achieved in only about a third of patients in specialized centers (Mampalam, T. J., et al., Transsphenoidal microsurgery for Cushing""s disease: A report of 216 cases, Ann. Intern. Med. 109:487-93 [1988]). Post-surgical persistence of ACTH hypersecretion requires pituitary-directed radiation to suppress tumor growth and hormonal levels. Radiation effects may not be manifest for several years, and are ultimately associated with pituitary damage and dysfunction in most patients (Brada, M., et al., The long-term efficacy of conservative surgery and radiotherapy in the control of pituitary adenomas, Clin. Endocrinol. 38:571-8 [1993]). Hypercortisolism, cortisol hypersecretion, may be completely resolved by adrenalectomy (surgical removal of one or both of the adrenal glands), but this approach does not suppress pituitary tumor growth, and is also associated with other co-morbidity (Trainer, P. J., et al., Cushing""s syndrome: Therapy directed at the adrenal glands, Endocrinol. Metab. Clin. North Am., 23:571-584 [1994]).
Medical therapy with cyproheptadine, an anti-serotonin agent, was used in the 1980""s to suppress ACTH secretion but ultimate efficacy was poor, and its use has been discontinued (Krieger, D. T., et al., Cyproheptadine-induced remission of Cushings disease, N. Engl. J. Med. 293:893-6 [1975]). Although the antifungal, ketoconazole, suppresses adrenal cortisol biosynthesis, the drug does not inhibit pituitary tumor growth or ACTH secretion, and idiosyncratic hepatic impairment limits its longterm use (Sonino, N., The use of ketoconazole as an inhibitor of steroid production, N. Engl. J. Med. 317:812-8 [1987]).
Pituitary tumors and the many disease conditions associated therewith have not heretofore been associated with peroxisome proliferator-activated receptor gamma (PPAR-xcex3). PPAR-xcex3 is a member of the nuclear receptor superfamily (Issemann, I., et al., Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators, Nature 347:645-660 [1990]; Schoonjans, K, et al., Peroxisome proliferator-activated receptors, orphans with ligands and functions, Curr. Opin. Lipidol. 8:159-166 [1997]), believed to function as a transcription factor mediating ligand-dependent transcriptional regulation (Kliewer, S. A., et al., Convergence of 9-cis retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their receptors, Nature 358:771-774 [1992]; Palmer, C. A. N., et al., Interaction of the peroxisome proliferator-activated receptor alpha with the retinoid X receptor alpha unmasks a cryptic peroxisome proliferator response element that overlaps an ARP-1-binding site in the CYP4A6 promoter, J. Biol. Chem. 270:16114-16121 [1995]; Tontonoz, P., et al., MPPARy2: tissue-specific regulator of an adipocyte enhancer, Genes Dev. 8:1224-34 [1994]). High affinity PPAR-xcex3 ligands include the insulin sensitizing thiazolidinedione compounds (TZD) (Spiegelman, B. M., PPAR-gamma: adipogenic regulator and thiazolidinedione receptor, Diabetes 47:507-514 [1998]; Kliewer, S. A., et al., A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor gamma and promotes adipocyte differentiation, Cell 83:813-819 [1995]; Forman, B. M., et al., 15-Deoxy-delta 12, 14-prostaglandin J1 is a ligand for the adipocyte determination factor PPAR gamma, Cell 83:803-812 [1995]). PPAR-xcex3 activation leads to adipocyte differentiation (Spiegelman, B. M., PPAR-gamma: adipogenic regulator and thiazolidinedione receptor, Diabetes 47:507-514 [1998]), glucose regulation (Saltiel, A. R., et al., Thiazolidinediones in the treatment of insulin resistance and type II diabetes, Diabetes 45:1661-9 [1996]), and inhibition of macrophage and monocyte activation (Ricote, M., et al., The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation, Nature 391:79-82 [1998]; Jiang, C., et al., PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines, Nature 391:82-86 [1998]). PPAR-xcex3 is expressed in breast, prostate and colon epithelium, and administration of synthetic PPAR-xcex3 ligands inhibits prostate, and colon tumor cell growth (Staels, B., et al., Activation of human aortic smooth-muscle cells is inhibited by PPAR-alpha but not PPAR-gamma activators, Nature 393:790-793 [1998]; Elstner, E., et al., Ligands for peroxisome proliferator-activated receptor-xcex3 and retinoic acid receptor inhibit growth and induce apoptosis of human breast cancer cells in vitro and in BNX mice. Proc. Natl. Acad. Sci. USA 95:8806-8811 [1998]; Kubota, T., et al., Ligand for peroxisome proliferator-activated receptor-xcex3 (troglitazone) has potent anti-tumor effects against prostate cancer both in vitro and in vivo, Cancer Res. 58:3344-3352 [1998]; Sarraf, P., et al., Differentiation and reversal of malignant changes in colon cancer through PPAR gamma, Nat. Med. 4:1046-1052 [1998]), and anti-angiogenic actions of these ligands have also been demonstrated (Xin, X., et al., Peroxisome proliferator-activated receptor xcex3 ligands are potent inhibitors of angiogenesis in vitro and in vivo, J. Biol. Chem. 274:9116-21 [1999]). In. U.S. Pat. No. 6,207,690, PPAR-xcex3 ligands were implicated in the treatment of cancers and climacteric. (See also U.S. Pat. No. 5,814,647).
There remains a need for a non-invasive treatment of pituitary tumors, including effective drug therapies for hormone-secreting pituitary tumors such as Cushing""s Syndrome. This and other benefits are provided by the present invention as described herein.
The present invention is based on the following discoveries: (1) that pituitary peroxisome proliferator-activated receptor gamma (also known as xe2x80x9cperoxisome proliferating-activator receptor gammaxe2x80x9d or xe2x80x9cPPAR-xcex3xe2x80x9d) expression is restricted primarily to ACTH-secreting cells of the normal human anterior pituitary; (2) that pituitary PPAR-xcex3 is abundantly expressed in human ACTH-, PRL-, LH-, GH-, and FSH-secreting pituitary tumors; (3) that PPAR-xcex3 ligands potently inhibit ACTH-, PRL-, LH-, GH- secreting pituitary tumor proliferation in vitro, and inhibit pituitary tumor growth in vivo; and (4) that rosiglitazone, a known PPAR-xcex3 ligand, administration suppresses 24 hour urinary cortisol excretion in Cushing""s disease. These results support the role for PPAR-xcex3 as a novel molecular target in the treatment of mammalian subjects afflicted with a pituitary tumor or Cushing""s syndrome.
The present invention provides methods for treating pituitary tumors, including ACTH-secreting pituitary tumors, in a mammal. The inventive methods involve administering to the mammal having a pituitary tumor a therapeutically effective amount of PPAR-xcex3 ligands. Such PPAR-xcex3 ligands include thiazolidinediones (TZDs), such as troglitazone, pioglitazone, and rosiglitazone.
Another aspect of the present invention includes a method for preventing the formation of a pituitary tumor in a mammal, comprising administering to a mammal at higher than normal risk for developing a pituitary tumor an effective amount of at least one peroxisome proliferator activated receptor gamma ligand. A further aspect of the present invention includes a method for preventing the recurrence of a pituitary tumor in a mammal. The method involves administering to a mammal, said mammal previously having had a detectable pituitary tumor eliminated, an effective amount of at least one peroxisome proliferator activated receptor gamma ligand.
Yet another aspect of the present invention is a method for treating a mammal, including a human, exhibiting one or more symptoms of Cushing""s syndrome (such as steroid hypersecretion and/or elevated urinary cortisol excretion) comprising administering to the subject a therapeutically effective amount of at least one PPAR-xcex3 ligand.